One hypothesis fo tumor promotion proposes that promoters function to stimulate proliferation of initiated cell populations which produces either (1) clonal selection of progressing cells or (2) increased probability of gene rearrangements or fixation of DNA damage. Recent work in this laboratory suggests that the promoting activity of phorbol esters in JB6 mouse epidermal cells is not due to a release from quiescence type of mitogenic stimulation by the tumor promoter. Evidence for this is: (1) some mitogen-resistant (M-) variants show promotable (P+) phenotype; and (2) di-2-ethylhexyl phthalate (DEHP) promotes anchorage-independence but does not function as a mitogen in JB6 cells. These 12-O-tetradecanoylphorbol-13-acetate (TPA) mitogen-resistant variants are currently being used to discover biochemical events which determine the mitogenic response. Two such events which appear to mediate the mitogenic response to TPA are epidermal growth factor (EGF) (or other growth factor) binding to EGF receptors and stimulated hexose transport. Supporting a requirement for EGF receptors in TPA mitogenesis is our recent observation that reconstitution of M-EGF receptorless cells with membranes containing EGF receptors restored not only binding and mitogenic response to EGF, but also mitogenic response to TPA. In support of a role for stimulated hexose transport is our observation that a mitogen-sensitive (M+) revertant of an M- cell line regained the stimulated hexose uptake response to TPA missing in the M- parental line.